Recent patents on cardiovascular drug discovery最新文献

Levosimendan is a calcium sensitizer with positive inotropic and vasodilating properties. It increases the sensitivity of troponin C for calcium, opens adenosine triphosphate-dependent potassium K(+) channels and inhibits phosphodiesterase III. Levosimendan is approved for use in cardiac failure but large clinical trials have raised doubts whether levosimendan is superior to β-adrenergic agonists regarding long-term survival of patients. Despite this controversy, there is growing evidence of beneficial effects of levosimendan in ischemia/reperfusion (I/R) injury due to its effect on K(+) channels. As a consequence, patents on K(+) channel agonists have been granted recently for reducing injury in organs or tissue in transplants and trauma therapy. Moreover, experimental studies and clinical trials have shown that levosimendan effectively inhibits cardiomyocyte apoptosis. The underlying molecular mechanism is currently unclear. However, it is tempting to assume that levosimendan inhibits cardiomyocyte apoptosis due to its beneficial effect on I/R injury. However, the link between these two phenomena has not been well established. This review summarizes experimental studies and clinical trials on the effects of levosimendan in I/R injury and apoptosis also discussing recent patents.

Vernakalant is a novel anti-arrhythmic drug, recently approved for the cardioversion of recent-onset atrial fibrillation. Its action is mainly due to the blockade of atrial-selective channels responsible of the ultra-rapid delayed rectifier current I(Kur), but has also important interactions with other channels and currents, such as I(Na) (inward sodium current), and I(KACh) (acetylcholine-regulated potassium current). Due to the relatively selective blockade of the I(Kur), vernakalant prolongs the effective refractory period of the atria with minimal effects on the ventricles, thus minimizing the risk of proarrhythmia. Thus far vernakalant has been tested in three placebo-controlled trials (ACT I, ACT II and ACT III) and in one amiodarone-controlled study (AVRO). Vernakalant has been demonstrated more effective than both placebo and amiodarone for the rapid conversion of atrial fibrillation, without significant adverse events. This article will review the recent patents on this novel atrial-selective agent, discussing its mechanisms of action and possible clinical applications in the real-world practice.

Ultrasound imaging is widely used worldwide principally because it is cheap, easily available and contains no exposure to ionizing radiation. The advent of microbubble ultrasound contrast has further increased the diagnostic sensitivity and specificity of this technique thus widening its clinical applications. The third generation of ultrasound contrast agents consist of sulphur hexafluoride microbubbles encased in a phospholipid shell. This review will elaborate on the pharmacology, safety profile and method of action of these agents. We also aim to discuss the ever expanding uses for contrast enhanced ultrasound in a number of clinical specialities which include the liver, kidney, prostate, sentinel node detection, vascular tree and endovascular stent surveillance. We will also discuss some of the recent patents regarding the future uses of ultrasound microbubble contrast and recent technological advances in clinical applications.

Matrix metalloproteinases (MMPs) have a pivotal role in the natural history of atherosclerosis and its cardiovascular consequences. Non-selective MMP inhibition with doxycycline appears as a potential strategy to reduce the residual risk observed in patients already at intensive lipid lowering strategies. However, specific MMPs have different and even contradicting roles in the natural history of atherosclerosis, rendering broad spectrum MMP inhibition an important yet somewhat simplistic approach towards residual risk reduction in coronary atherosclerosis. Overall, the balance of non-selective MMP inhibition might shift to the favorable side in particular settings such as in acute coronary syndromes, where in addition to its potential plaque stabilization properties, doxycycline shows promise in preventing ischemia-reperfusion injury and left ventricular remodeling. Nevertheless, to date, most animal models used do not represent advanced coronary atherosclerosis seen in humans, and large and well-designed clinical studies are lacking. We discuss the available evidence and recent patents supporting the role of doxycycline in atherosclerosis.

Recent advances in technology and novel pharmaceutical research findings have added new grounds in the fields of medical treatment and quality of life of patients diagnosed with pulmonary arterial hypertension (PAH). Collective assessment of new data is mandatory and useful for specialist medical doctors. This review aims to present the latest therapeutic developments of the last two years (2009-2010) in PAH. Moreover, recent patents (of the year 2010) regarding therapeutic novelties in PAH that expand treatment modalities, are hereby presented.

A great number of observations show that cardiovascular damage from smoking may be a consequence of both active and passive smoking exposure. Some findings identify an increase in cardiovascular events in active smokers as well as in non-smokers exposed to passive smoking. The type and extension of damage seem to be similar qualitatively either in active smokers or in exposed never smokers. Artery vessels and myocardium feel particularly the effects of smoking. Ischaemic heart disease and atherosclerosis progression are the common alterations observed. Individuals exposed to both active and passive smoking feel the adverse effects of smoking. Result of the interaction consists primarily of increased rate of clinical events whereas the type of anatomical alterations is similar to those which characterize respectively isolated exposure to active or passive smoking. However, the extension of cardiovascular damage may vary even if, usually, in the same location of pre-existing lesions. The article also presents some of the patents regarding the effects of smoking on cardiovascular system.

The dual endothelin receptor antagonist, bosentan, is an orally active therapy, which has been proved to be effective in the treatment of pulmonary arterial hypertension (PAH). This review critically addresses and highlights pharmacological aspects of bosentan such as safety, tolerability and drug interactions. The biological basis of its mode of action is demonstrated in preclinical studies on animal models of PH and an up-to-date review of clinical data is provided, supporting its practical use with a view to achieve optimal treatment goals. Major pivotal randomized placebo-control clinical trials are discussed, together with recently published data concerning its promising role as part of combination therapy. Furthermore, recent patents of novel pharmaceutical interventions in the field of PAH, expanding treatment options, are presented.

Left ventricular remodelling is a progressive process, which starts immediately after acute myocardial infarction and evolves in the chronic phase of heart failure. It is characterized by left ventricular chamber dilatation and increased wall stress, which results in alteration of the contractile properties of the non-infarct zone and impairment of the systolic and diastolic performances of the left ventricle. Neurohormonal activation and increased sympathetic stimulation are among the factors that have been linked to the development and progression of left ventricular dysfunction after acute myocardial infarction. The present review will address recent insights from new patents and experimental studies of drugs, which ought to prevent left ventricular remodelling. Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers and Beta-Blockers have been proven effective in modulating the process of remodelling and in reducing the occurrence of adverse events. However, in most of the trials high risk patients have been excluded, and uncertainty still exists regarding a number of clinically relevant questions. Data from experimental studies have identified new targets for interventions to prevent reverse left ventricular remodelling, i.e. stem cell transfer, activation of cardiac and leukocyte-dependent oxidant stress pathways, inflammatory pathway activation, matrix-metalloproteinase activation.

The incidence of cardiovascular disease is increasing worldwide. Despite many new developments in 60(th) medical and surgical specialities, a substantial number of cardiac patients are not suitable candidates for one of the current treatment options. This "no-option" subgroup of patients is a driving influence in the rapidly developing field of angiogenesis. In this review, we discuss the different modalities of treatment being tried for these patients and the patents which have been filed to improve cardiac angiogenesis.

Despite the availability of dual antiplatelet therapy comprised of aspirin and clopidogrel, there is still significant unmet medical need for treating and preventing arterial thrombotic diseases. To achieve further reduction of cardiovascular events without exceeding bleeding tolerability and safety limits, novel antiplatelet strategies might need to trade in antiplatelet efficacy by partial inhibition of an important platelet activation pathway or by differentially targeting pathological versus physiological thrombogenesis pathways. Thrombin, the central enzyme in coagulation and the most potent platelet agonist tested in vitro, is one of the key factors driving the formation of occlusive thrombi. Platelet thrombin receptors, namely protease-activated receptor 1 (PAR-1) and protease-activated receptor 4 (PAR-4), act in concert to elicit robust platelet responses to thrombin. PAR-1 is the high affinity thrombin receptor and represents a novel antithrombotic target. PAR-4 is a low affinity thrombin receptor with less understood function. This review discusses the genetic and pharmacological evidence for PAR-1 target validation and highlights the progresses and challenges in developing oral PAR-1 antagonists, especially SCH 530348 from Merck/Schering-Plough and E-5555 from Eisai Co. Recent patents disclosing several novel chemical series of PAR-1 antagonists from Sanofi-Aventis and Pierre Fabre are also presented.